Subgenual-Prefrontal Interactions and Cortical Inhibition Drive iTBS Efficacy in Treatment-Resistant Depression

Depression remains a significant global health challenge, with Intermittent Theta Burst Stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) as a promising intervention for treatment-resistant depression. However, the neurophysiological mechanisms driving its clinical efficacy are not fully understood. Here, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) with whole-brain computational modeling to investigate iTBS effects in a cohort of 90 participants. Before iTBS, responders exhibited a unique brain state marked by opposite directional interactions between the subgenual cingulate (SGC) and DLPFC, a pattern absent in non-responders. Following iTBS, responders demonstrated significant divergence from baseline neuronal dynamics, especially between 50-120 ms post-stimulation, suggesting enhanced neuroplasticity. Furthermore, responders exhibited a power reduction in the 3-10 Hz range, associated with increased cortical inhibition and a lowered excitation-inhibition ratio. These results suggest that iTBS restores balance within prefrontal-subgenual networks and enhances cortical inhibition, which may be crucial mechanisms underlying clinical improvements in responders.